The goal of this proposal is to delineate the viral genes that lead to severe acute respiratory syndrome (SARS) utilizing a novel rodent model of SARS. SARS infected over 8,000 persons globally with over 700 deaths. We propose to use a MHV-1 infected mouse model of SARS developed by our group to identify coronavirus genes that contribute to this severe pulmonary disease. The first aim of the research will utilize reverse genetics to examine the roles of structural proteins spike (S), matrix (E) and nucleocapsid (N) proteins and non-structural accessory proteins in the pathogenesis of SARS-like pneumonitis in our model. These studies will employ a targeted recombination approach. Chimeric MHV-1/non-pneumotropic recombinant viruses will be used to determine the MHV-1 genes necessary for targeting to the lung and for the development of SARS like pulmonary disease. In the second aim we will investigate the hypothesis that the ACE2 receptor binding domain of the SARS-CoV spike protein (Srbd) contributes to SARS pathogenesis by abrogating the pneumoprotective effect of ACE2 in addition to its role in viral attachment to cells. MHV-1/SARS-Srbd recombinants will be isolated and their ability to enhance virulence and cause lethal SARS-like pulmonary disease in otherwise MHV-1 resistant mice will be determined. These studies will identify MHV-1 genes that are necessary and/or sufficient for the unique SARS-like pathology induced by this virus, and assess the role of the SARS-CoV Srbd in pathogenesis independent of its role as a viral attachment protein in a mouse model of SARS. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to delineate the viral genes that lead to severe acute respiratory syndrome (SARS) utilizing a novel rodent model of SARS. SARS infected over 8,000 persons globally with over 700 deaths. We will use a related coronavirus, mouse hepatitis virus type 1 (MHV-1), that produces a disease in mice that mimics SARS. We use this newly developed mouse model of SARS to identify coronavirus genes that contribute to this severe pulmonary disease. This information should be useful in advancing our understanding of SARS and other coronavirus pulmonary infections and may provide a basis for developing future therapeutic approaches to these diseases.